Ch 10 Controlling Microbial Growth in the Body: Antimicrobial Drugs

Controlling Microbial Growth in the Body: Antimicrobial Drugs

The History of Antimicrobial Agents

The development of antimicrobial drugs revolutionized the treatment of infectious diseases. Key historical figures contributed to the discovery and advancement of these agents.

• Paul Ehrlich: Proposed the concept of “magic bullets”—chemicals that selectively target pathogens. He developed arsenic compounds effective against microbes.

• Alexander Fleming: Discovered penicillin, the first true antibiotic, produced by the fungus Penicillium chrysogenum.

• Gerhard Domagk: Discovered sulfanilamide, the first widely used synthetic antimicrobial.

• Selman Waksman: Coined the term “antibiotics” for antimicrobial agents produced naturally by organisms.

Definitions:

• Drugs: Chemicals that affect physiology in any manner.

• Chemotherapeutic agents: Drugs that act against diseases.

• Antimicrobial agents (antimicrobials): Drugs that treat infections.

Sources of Antibiotics and Semisynthetics

Antibiotics are naturally produced by microorganisms, while semisynthetics are chemically modified derivatives. Synthetics are entirely synthesized in the laboratory.

Microorganism	Antimicrobial
Penicillium chrysogenum	Penicillin G
Penicillium griseofulvum	Griseofulvin
Acremonium spp.	Cephalosporin
Amycolatopsis orientalis	Vancomycin
Bacillus polymyxa	Polymyxin
Streptomyces griseus	Streptomycin
Streptomyces aureofaciens	Tetracycline
Streptomyces venezuelae	Chloramphenicol
Streptomyces avermitilis	Ivermectin

Mechanisms of Antimicrobial Action

Principle of Selective Toxicity

Selective toxicity refers to the ability of an antimicrobial drug to harm the pathogen without damaging the host. This principle is fundamental to effective chemotherapy.

• Antibacterial drugs are the most numerous and diverse due to the significant differences between bacterial and human cells.

• Fewer drugs are available for eukaryotic pathogens (fungi, protozoa, helminths) and viruses due to similarities with host cells.

Major Mechanisms of Action

Antimicrobial drugs target pathogens through several mechanisms:

• Inhibition of cell wall synthesis

• Inhibition of protein synthesis

• Disruption of cytoplasmic membrane

• Inhibition of metabolic pathways

• Inhibition of nucleic acid synthesis

• Prevention of pathogen attachment or entry into host cell

Inhibition of Cell Wall Synthesis

Many antimicrobials prevent the synthesis of peptidoglycan, a key component of bacterial cell walls, leading to cell lysis.

• Beta-lactams (e.g., penicillins, cephalosporins, carbapenems) bind to enzymes that cross-link NAM subunits, weakening the cell wall.

• Vancomycin and cycloserine interfere with bridges between NAM subunits in Gram-positive bacteria.

• Bacitracin blocks transport of NAG and NAM from the cytoplasm.

• Isoniazid and ethambutol disrupt mycolic acid formation in mycobacteria.

• These drugs are effective only against growing cells and do not affect existing peptidoglycan.

Inhibition of fungal cell wall synthesis: Echinocandins inhibit glucan synthesis, a component unique to fungal cell walls.

Inhibition of Protein Synthesis

Antimicrobials can selectively target bacterial ribosomes (70S) without affecting eukaryotic ribosomes (80S), though mitochondrial ribosomes may be affected.

• Aminoglycosides (e.g., streptomycin) cause misreading of mRNA.

• Tetracyclines block tRNA docking.

• Chloramphenicol blocks peptide bond formation.

• Macrolides and lincosamides block ribosomal movement.

• Oxazolidinones prevent initiation of translation.

• Mupirocin inhibits isoleucyl-tRNA synthetase in Gram-positive bacteria.

Disruption of Cytoplasmic Membranes

Some drugs compromise membrane integrity, causing cell death.

• Polymyxins disrupt Gram-negative bacterial membranes (toxic to kidneys).

• Nystatin and amphotericin B bind to ergosterol in fungal membranes, forming pores.

• Azoles and allylamines inhibit ergosterol synthesis in fungi.

Inhibition of Metabolic Pathways

Antimetabolic agents target pathways unique to pathogens.

• Sulfonamides are structural analogs of PABA and inhibit folic acid synthesis, essential for nucleotide production in bacteria and protozoa.

• Trimethoprim also interferes with nucleotide synthesis.

• Atovaquone disrupts electron transport in protozoa and fungi.

• Antiviral agents (amantadine, rimantadine) prevent viral uncoating; protease inhibitors block HIV replication.

Inhibition of Nucleic Acid Synthesis

Some drugs block DNA replication or RNA transcription, often affecting both prokaryotic and eukaryotic cells.

• Quinolones and fluoroquinolones inhibit DNA gyrase in bacteria.

• Nucleotide/nucleoside analogs distort nucleic acid structure, blocking replication and transcription (especially effective against viruses and cancer cells).

• Reverse transcriptase inhibitors target HIV replication.

Prevention of Virus Attachment, Entry, or Uncoating

Attachment antagonists block viral proteins or host receptors, preventing infection. Examples include pleconaril (blocks attachment) and arildone (prevents uncoating).

Clinical Considerations in Prescribing Antimicrobial Drugs

Spectrum of Action

Antimicrobials vary in the range of pathogens they affect.

• Narrow-spectrum drugs target specific organisms, minimizing disruption of normal flora.

• Broad-spectrum drugs target a wide range of organisms but may cause superinfections by disrupting normal microbiota.

Effectiveness

Several laboratory tests assess antimicrobial efficacy:

• Diffusion susceptibility (Kirby-Bauer) test: Measures zones of inhibition around antibiotic disks.

• Minimum inhibitory concentration (MIC) test: Determines the lowest drug concentration that inhibits visible growth.

• Etest: Combines aspects of Kirby-Bauer and MIC tests using a gradient strip.

• Minimum bactericidal concentration (MBC) test: Identifies the lowest concentration that kills the organism.

Routes of Administration

Antimicrobials can be administered in various ways, affecting their distribution and effectiveness:

• Topical: For external infections.

• Oral: Convenient and self-administered, but absorption may be variable.

• Intramuscular (IM): Delivers drug into muscle tissue.

• Intravenous (IV): Provides rapid and high drug levels in the bloodstream.

Safety and Side Effects

Antimicrobial therapy can cause adverse effects:

• Toxicity: May affect kidneys, liver, or nerves; special caution for pregnant women.

• Therapeutic index (TI): Ratio of tolerated dose to effective dose; higher TI indicates greater safety.

• Allergies: Rare but potentially life-threatening (e.g., anaphylactic shock).

• Disruption of normal microbiota: May lead to secondary infections or superinfections, especially in hospitalized patients.

Resistance to Antimicrobial Drugs

The Development of Resistance in Populations

Microbial resistance arises through genetic changes and horizontal gene transfer.

• Resistance can develop via new mutations or acquisition of resistance (R) plasmids through transformation, transduction, or conjugation.

Mechanisms of Resistance

Microorganisms employ several strategies to resist antimicrobials:

• Enzyme production that destroys or deactivates the drug (e.g., β-lactamase).

• Prevention of drug entry into the cell.

• Alteration of drug targets.

• Modification of metabolic pathways.

• Efflux pumps expel the drug from the cell.

• Biofilm formation increases resistance.

• Production of proteins (e.g., MfpA in Mycobacterium tuberculosis) that protect drug targets.

Multiple Resistance and Cross Resistance

Pathogens may acquire resistance to multiple drugs, especially in healthcare settings where antimicrobials are frequently used. Cross resistance occurs when resistance to one drug confers resistance to similar drugs.

Retarding Resistance

Strategies to slow the development of resistance include:

• Maintaining high drug concentrations in patients to ensure pathogen elimination.

• Using combinations of antimicrobials (synergism enhances effect; antagonism reduces efficacy).

• Limiting antimicrobial use to necessary cases.

• Developing new drugs and modifying existing ones.

Additional info: This guide covers the essential concepts and mechanisms related to antimicrobial drugs, their clinical use, and resistance, as outlined in a typical microbiology curriculum.